I-dehydro and i



United States Patent No Drawing. Filed June 16, 1961, Ser. No. 117,533 6 Claims. (Cl. 260-3973) The present invention relates to unsaturated 3,15,20- trisoxygenated steroids of the pregnane series and, more particularly, to l-dehydro and 1,6-dehydro derivatives of 15-oxygenated pregn-4-ene-3,20-diones as represented by the structural formulae CH3 X and wherein X is a carbonyl, ,B-hydromethylene, or p-(lower alkanoyl) oxymethylene group.

The lower alkanoyl radicals encompassed by X are eX- emplified by formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof.

The compounds of this invention are conveniently prepared by utilizing 15B-hydroxypregn-4-ene-3,20-dione and 1SB-hydroxypregna-4,6-diene-3,ZO-dione as starting materials. The reaction of these. compounds with a dehydrogenating agent produces the corresponding l-dehydro derivatives as is typified by the dehydrogenation of 15/3- hydroxypregn-4-ene-3,20-dione by treatment with 2,3-dichloro-5,6-dicyanoquinone in an organic solvent medium to yield 1SB-hydroxypregna-l,4-diene-3,20-dione. This 1,2-dehydrogenation reaction can be accomplished also by the use of suitable microorganisms, for example, Corynebacterium simplex, as well as by means of other chemical reagents such as selenium dioxide.

The instant 15-oxo compounds can be obtained by oxidation of the aforementioned 15,3-hydroxy substances of this invention. Typically, 1SB-hydroxypregna-l,4,6-triene, 3,20-dione in acetone is treated with aqueous chromic acid to afford pregna-1,4,6-triene-3,15,20-trione.

The instant lSfl-hydroxy compounds can be converted to the corresponding alkanoate esters by reaction with a lower alkanoic acid anhydride in the presence of a suitable acid acceptor. As a specific example of this process, 1Sfl-hydroxypregna-l,4-diene-3,20-dione is converted to lSfi-acetoxypregna-l,4-diene-3,20-dione by reaction with acetic anhydride and pyridine.

The compounds of this invention are useful as antibacterial agents as is evidenced by their ability to inhibit the growth of Diplococcus pneumonz'ae. They display also valuable pharmacological properties. They are, for example, potent oral diuretic agents in view of their abil- 3,123,622 Patented Mar. 3, 1964 ice ity to block the efiect of aldosterone-like substances on urinary sodium.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade 0.). Quantities of materials are expressed in parts by weight unless otherwise noted.

, 3,20-dione, 4.1 parts of 2,3-dichloro-5,6-dicyanoquinone,

and 61.8 parts of dioxane is heated at reflux for about 5 /2 hours, then allowed to cool to room temperature and filtered. 'Ihe filtrate is concentrated to dryness at reduced pressure, and the resulting residue is crystallized first from acetone, then from methylene chloride-acetone to afford ISB-hydroxypregna-l,4-diene-3,20 dione, M.P. about 230-233".

Example 2 To a solution of 1.6 parts of ISB-hydroxypregna-IA- diene-3,20-dione in 200 parts of acetone, cooled by means of an ice bath, is added dropwise 1.5 parts of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The reaction mixture is stirred for about 5 minutes, then poured into water and extracted with methylene chloride. sodium sulfate and concentrated to dryness at reduced pressure. Recrystallization of the residue from acetoneether produces pregna-1,4-diene-3,15,20-trione, M.P. about 207 -209.5

Example 3 A mixture of 5.17 parts of 15fi-hydroxypregna-4,6-dione-3,20-dione, 4.1 parts of 2,3-dichloro-5,6-dicyanoquinone, and 60 parts of dioxane is heated at reflux for about 4 hours, then cooled and filtered. The filtrate is concentrated to dryness in vacuo, and the residue is triturated with acetone-ether, then crystallized from methylene chloride-methanol-acetone to yield 15 8-hydr0xypregna-1,4,6-triene-3,20-dione, M.P. about 241.5244.

Example 4 To a slurry of one part of 1Sp-hydroxypregna-1,4,6-trieriene-3,20-dione in 104 parts of acetone is added 0.89 part by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid, and the resulting solution is stirred for about 5 minutes longer, than diluted with water. This aqueous mixture is partially concentrated, then is extracted with methylene chloride. The organic solution is concentrated to dryness at reduced pressure, and the resulting residue is dissolved in ethyl acetate-benzene, then is chromatographed on silica gel. Elution with 20% ethyl acetate in benzene followed by recrystallization from methylene chloride afiords pregnal,4,6-triene-3,15,20-trione, M.P. about l86187.5.

Example 5 A mixture of one part of lSB-hydroxypregna-1,4-diene- 3,20-dione, 10 parts of acetic anhydride, and 20 parts of pyridine is heated at about to achieve homogeneity, then is stored at room temperature for about 7 days. Water is added and the resulting aqueous mixture is made slightly alkaline by the addition of sodium carbonate. Extraction with methylene chloride afiords an organic so lution, which is washed with water, and evaporated to dryness at reduced pressure. The resulting residue is adsorbed on silica gel, and the chromatographic column is The organic solution is dried over anhydrouseluted with ethyl acetate-benzene mixtures to alford 15B- acetoxypregna- 1 ,4-diene-3,20-dione.

By substituting one part of 15/8-hydroxypregna-l,4,6- triene-3,20-dione and otherwise proceeding according to the herein described processes, 15fl-acetoxypregna-1,4,6- triene-3,20-dione is obtained.

Example 6 wherein X is selected from the group consisting of car- (i bonyl, B-hydroxymethylene, and B-(loweralkanoyDoxymethylene radicals.

2. A compound of the structural formula 10 CH3 i wherein X is selected from the group consisting of carbonyl, ,B-hydroxymethylene, and ,B-(lower alkanoy1)oxymethylene radicals.

3. Pregna-1,4-diene-3,15,20-trione.

4. ISB-hydroxypregna-l,4-diene-3,20-dione. 5. Pregna-1,4,6-triene-3,15,20-trione.

6. 15/3-hydroxypregna-1,4,6-triene-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND OF THE STRUCTURAL FORMULA 